Novel Role of SEL1L-HRD1 ERAD in Pathogenesis of Alzheimer?s Disease ABSTRACT Neurons face a complex challenge of balancing protein folding and degradation in the endoplasmic reticulum (ER). Indeed, altered ER proteostasis has been implicated in the pathogenesis of neurodegeneration including Alzheimer?s disease; however, the underlying molecular mechanisms remain largely unknown. To date, the role of ER-associated degradation (ERAD), the first line of defense by clearing misfolded ER proteins for cytosolic proteasomal degradation, in neurons remains unknown. Sel1L- Hrd1 protein complex represents the most conserved ERAD branch with Sel1L being the cofactor for the E3 ligase Hrd1. We recently generated pan-neuron-specific Sel1L-deficient (Sel1LSynCre) mice and found that, even before weaning, Sel1LSynCre mice exhibit signs of neurodegeneration, pointing to a cell-autonomous role of Sel1L in neuronal function in neurodegeneration. Providing further support to clinical relevance and importance of Sel1L, Sel1L SNP has identified in Finnish canines suffering early-onset cerebellar ataxia. In this administrative supplement, we propose to test an overarching hypothesis that Sel1L-Hrd1 ERAD plays a crucial role in neurodegeneration including Alzheimer?s disease by preventing the accumulation and aggregation of misfolded proteins in the ER, thereby ensuring biogenesis of nascent receptor(s) and neurotransmitter(s). Taking advantage of the advances obtained in this parent grant, we propose to address two of the following Aims: (1) determine whether and how SEL1L-HRD1 ERAD expression is altered in AD neurons; and (2) Identify the SEL1L-interacting network and ERAD substrates in healthy and AD neurons. Indeed, this study is made possible by our recent effort that has led to the generation and validation of several human SEL1L-specific antibodies for both immunoprecipitation and immunostaining. In completing this project, we will not only provide novel insights into the molecular events underlying SEL1L-HRD1 ERAD function in maintaining neuronal health, but also identify potential targets for manipulating the turnover of nascent ER proteins as an approach for the treatment of neurodegeneration.